Project Summary/Abstract Fluorescence has significant potential for biomedical imaging applications because of the relatively low cost of imaging equipment, the nominal toxicity of non-ionizing radiation (i.e., light), the potential for molecular imaging using target-specific contrast agents, and the prospect of multiplexed imaging using discretely colored fluorophores. Molecules common in biological tissues including lipids, water, and hemoglobin scatter and absorb light, rendering tissue opaque to visible wavelengths, but longer, near infrared (NIR) wavelengths penetrate deeper, giving us optical windows into the body. The first, second, and third NIR optical windows (NIR-I, II, and III) each have advantages ranging from use with accessible and economical Si detectors (NIR-I) to a reduction in scattering, and thus a marked improvement in resolution, in the NIR-II and III. To see inside a tissue, we require bright, photostable, highly absorbing, NIR fluorophores. In addition, the regular clinical use of any contrast agent requires that it is biocompatible and removed from the body following its use. We propose a new materials development effort to synthesize biocompatible and biodegradable semiconductor QDs that can be tuned for imaging in the NIR-I, II, or III. We propose a novel, optically active semiconductor nanoparticle that fully degrades in vivo for clinical molecular imaging. Inorganic contrast agents like semiconductor quantum dots (QDs) have been the focus of extensive biomedical research, but hold little promise for clinical translation because the materials comprise toxic constituents. Even inert, seemingly biocompatible inorganic materials like gold nanoparticles carry the clinical risk of accumulating indefinitely in tissues like the liver. This is in stark contrast to the only inorganic nanoparticle that has been FDA-approved to date: iron oxide nanoparticles (IONs) for MRI contrast and the treatment of anemia. The absence of heavy metals in IONs avoids toxicity, while degradation and bile excretion circumvent the potentially severe kidney strain experienced by patients receiving molecular contrast agents. This material profile inspires our innovative approach to reinventing QDs for clinical optical imaging. We hypothesize that heavy metal-free nanoparticles comprising only bioessential elements will be degraded and excreted just like iron oxide. The choice of a material with a small bandgap (0.6 eV) indicates that the absorption and emission will be size-tunable through NIR-I, II, and III wavelength regimes, enabling paradigm shifting levels of light penetration through tissues and clarity in fluorescence imaging. We will use computational approaches like density functional theory (DFT) modeling of various crystal structures to predict and optimize nanomaterial optical properties to rationally design semiconductor nanoparticles for clinical applications. Through this Exploratory Technology Development R21, we will synthesize and characterize novel semiconductor nanoparticles that address current limitations in function, toxicity, and bioaccumulation through their photoluminescence in the NIR-I, II, and III regimes, composition of bioessential elements, and capacity for in vivo degradation and excretion.